Reversible Myeloperoxidase Inhibition by Benzodioxole Carboxamides: Insights from In Silico and InVitro Studies.

Myeloperoxidase (MPO), a key pro-inflammatory enzyme, plays a pivotal role in the progression of cardiovascular diseases (CVD), notably atherosclerosis. Herein, we report the synthesis and biological screening of nitro- and amino-substituted benzo[1,3]dioxole-5-carboxamide derivatives (3a–3h and 4a–4h) as potential MPO inhibitors. Most molecules displayed favorable pharmacokinetic properties and exhibited promising in vitro inhibitory activity with compounds 3f (IC50 = 10 ± 0.27 μM) and 4f (IC50 = 11.53 ± 0.12 μM) emerging as potent leads for MPO inhibition. 3f and 4f significantly attenuated HOCl production in the taurine assay, effectively prevented oxidation of HDL, and controlled lipid peroxidation, highlighting their anti-atherogenic potential. The lead molecules effectively modulate ROS levels and demonstrate lower cytotoxicity in the MTT assay. Collectively, these findings showcase benzodioxole-carboxamide scaffolds as a new chemotype of MPO inhibitors, offering a promising avenue for the development of MPO-targeted anti-inflammatory therapeutics.